Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design

Abstract

Background: Heart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively.

Methods: The REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others.

Conclusions: This trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF. Trial registration Clinical Trials.gov: NCT02397421. Registered 12th March 2015.

Keywords: Cardiac MRI; Cardiopulmonary exercise testing; Diabetes; Heart failure; Mechanistic trial; SGLT2 inhibitor.

Figures

Fig. 1

Normal renal tubular resorption of glucose. The figure above depicts the physiological resorption of glucose in the PCT of the nephron. SGLT2 co-transporters located at the S1 and S2 segments of the PCT are responsible for 90 % of the resorbed glucose, whereas SGLT1 co-transporters remove the remainder in the S3 segment. The diagram also identifies the site at which SGLT2 inhibitors act. PCT proximal convoluted tubules

Fig. 2

Study design flowchart. HF Heart failure; LVESV Left ventricular end systolic volume; LVEDV Left ventricular end diastolic volume; LV Left ventricular; LVEF Left ventricular ejection fraction; MRI Magnetic resonance imaging; QOL Quality of life

Fig. 3

REFORM trial hypothesis. The figure above explains the hypothesis of the REFORM trial where reduction in pre and afterload as well as improvement in exercise capacity and weight loss will all contribute to improvement in heart failure. These features will be measured by cardiac MRI, CPEX, 6MWT and BCA to determine their exact contribution to cardiac function. CPEX cardio-pulmonary exercise test; 6MWT 6 min walk test; BCA body composition analysis; V02 Max Maximum oxygen consumption; Ve minute ventilation; VC02 carbon dioxide production